1. Field of the Invention
The present invention provides methods and compositions for identifying human subjects with an increased risk of having essential hypertension. In particular, this invention relates to the identification and characterization of polymorphisms in the human tissue kallikrein gene promoter correlated with increased or decreased risk of developing essential hypertension.
2. Background Art
The tissue kallikrein-kinin system has long been implicated in blood pressure regulation by genetic and physiological studies. Urinary excretion of tissue kallikrein is significantly lower in patients with essential hypertension (Elliot et al., 1934; Carretero et al., 1971; Margolius et al., 1971; Margolius et al., 1974) and in genetically hypertensive rats (Carretero et al., 1976; Carretero et al., 1978; Ader et al., 1986; Ader et al., 1987). Total urinary tissue kallikrein excretion was also found to be lower among individuals with parental hypertension than it was in individuals with two normotensive parents (Williams et al., 1987). Transgenic mice over-expressing the human tissue kallikrein gene have been shown to exhibit a hypotensive phenotype (Wang et al., 1994; Song et al., 1995). Further, a study involving 57 Utah pedigrees indicates that a dominant allele expressed as high total urinary kallikrein excretion may be associated with decreased risk of essential hypertension (Berry et al., 1989).
Identification of DNA polymorphisms provides an efficient way to study the association of genes and diseases by linkage analysis. The human tissue kallikrein gene is located on the long arm of chromosome 19 q13.3-13.4 (Evans et al., 1988). Although a TaqI restriction fragment length polymorphism (RFLP) was found at this locus in a Norwegian population (Berge and Berg, 1991), this genetic marker has only two polymorphisms with unfavored allelic frequencies, making it unsuitable for genetic studies. No significant linkage was found between blood pressure and the kallikrein gene using this marker (Berge and Berg, 1993). A polymorphic microsatellite marker close to the tissue kallikrein gene locus has been identified which is useful for linkage analysis (Richards et al., 1991). However, no previous studies have demonstrated a correlation between specific polymorphisms in the tissue kallikrein gene and blood pressure.
The present invention overcomes this shortcoming by providing methods and compositions for identifying individuals having an increased or decreased risk of developing essential hypertension based on analysis and characterization of a highly polymorphic locus in the promoter region of the human tissue kallikrein.